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Patients with high-risk gastrointestinal stromal tumors (GISTs) had a 60% improvement in 3-year disease-free survival (DFS) with 6 versus 3 years of maintenance imatinib, a randomized trial showed.

DFS at 3 years increased from 55% with 3 years of imatinib maintenance to 87% with 6 years of maintenance therapy. Patients with an estimated 35-70% risk of relapse derived the most benefit from extended maintenance, although patients with an estimated risk >70% had numeric improvement with extended maintenance therapy. Further analysis showed that patients with an estimated risk of recurrence >70% and no rupture at surgery benefited substantially from extended maintenance but not the subgroup with rupture.

Data for the secondary endpoints of time to imatinib resistance and overall survival (OS) remain immature, reported Jean-Yves Blay, MD, PhD, at University Claude Bernard in Lyon, France, during the European Society for Medical Oncology (ESMO) .

"Extending the duration of adjuvant imatinib from the standard 3 years to 6 years confers a significant reduction in the risk of recurrence or death," Blay said. "It was nice to see that the median DFS of the group of patients who reinstated imatinib at progression was 40 months, very consistent to what is being reported in the first-line setting, indicating that probably the outcome of patients relapsing in terms of survival will be the same as in patients without relapse. This will obviously require additional follow-up but it's really reasonable to assume that resistance to subsequent treatment will emerge in these patients as well."

"The results of the support 6-year duration of adjuvant imatinib for high-risk GIST, with a relapse risk [higher than] 35%," he added.

The results are promising and in line with what was expected, said ESMO invited discussant Hans Gelderblom, MD, of Leiden University Medical Center in the Netherlands. The trial was adequately powered to evaluate DFS but still was the smallest adjuvant study with the shortest follow-up, making subgroup analyses problematic.

Additionally, the study left several key questions unanswered: lack of significant benefit in the overall high-risk population and in patients with tumor rupture; improved outcomes with higher toxicity, requiring a quality-of-life assessment; application of the study to a real-world setting with older patients who have multiple comorbidities; and half the patients are probably already cured (in 3 months) but others do respond later.

"The main point in my view is there is no overall survival benefit yet, so this is not practice-changing, yet," said Gelderblom.

Some answers might come from the study, which will assess 3 versus 5 years of imatinib maintenance in high-risk patients.

"It would be really interesting to combine all the adjuvant studies and look in more detail at the mutations, the real risk factors, using the novel nomograms and to understand better what we are doing and which patients should have adjuvant imatinib and for how long," Gelderblom added.

Three years of adjuvant maintenance has been standard of care for high-risk GIST; however, about half the patients relapse after discontinuation of the tyrosine kinase inhibitor. ImadGIST was designed to determine whether continuing maintenance imatinib beyond 3 years would improve DFS in high-risk, KIT-positive GIST.

Investigators enrolled patients with fully resected GIST and ≥35% risk of relapse. All patients received imatinib for 3 years after surgery, and then were randomized to discontinuation of treatment or continuation for another 3 years. Patients in the control arm who recurred outside the randomized design could have imatinib reintroduced.

The primary objective was 3-year DFS. Secondary objectives included OS, safety and tolerance, time to secondary resistance to imatinib, and quality of objective response after reintroduction of imatinib in case of recurrence. The trial had statistical power to detect a hazard ratio of 0.462, representing an improvement in DFS of 75% with 3 years of imatinib to 90% with prolonged maintenance.

Data analysis included 136 patients, 71 randomized to 6 years of imatinib. About a third of patients in the control arm had an estimated recurrence risk of 35-70% versus 44% in the study arm, and 57% of the control arm versus 48% of the study arm had patients with an estimated recurrence risk >70%. About 84% of patients had KIT exon 11 mutations.

The primary analysis showed that patients who received 6 years of imatinib had a DFS hazard of 0.40 (95% CI 0.20-0.67, P=0.008). Analysis of results by risk stratification showed that eight of 21 patients with estimated risk of 35-70% in the control group had recurrences versus one of 31 in the extended-therapy arm, which translated into a hazard ratio of 0.08 (P=0.0016). Among patients with estimated risk >70%, 20 of 37 in the control arm and 14 of 34 in the study arm had recurrences (HR 0.68, P=0.2581).

Among control patients who relapsed after imatinib interruption at 3 years, median progression-free survival was 40 months, similar to what has been reported for patients in first line, said Blay.

Extended imatinib maintenance was associated with substantially more adverse events (all grades), including muscle spasms (51% vs 22%), diarrhea (44% vs 23%), asthenia (30% vs 17%), abdominal pain (21% vs 11%), eyelid edema (20% vs 3%), and myalgia (16% vs 8%).

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